title: A new DNA gyrase inhibitor subclass of the cyclothialidine family based on a bicyclic dilactam-lactone scaffold. Synthesis and antibacterial properties.
abstract: The DNA gyrase inhibitor cyclothialidine had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance to clinically used drugs. Bicyclic lactone derivatives containing in their 12-14-membered ring a thioamide functionality were reported previously to exhibit potent antibacterial activity against gram-positive bacteria. Moderate in vivo efficacy, however, was demonstrated only for derivatives bearing hydrophilic substituents, which were found to have a favorable impact on pharmcokinetics, and to reduce metabolic degradation, in particular glucuronidation. The incorporation of an additional amide unit into the 14-membered monolactam-lactone scaffold of cyclothialidine analogues provided a new "dilactam" subclass of DNA gyrase inhibitors of inherently higher polarity. After adjusting their lipophilicity by methyl-halogen exchange at the benzene ring, compounds of this series did not require the thioamide functionality to exert a decent antibacterial potency and consequently exhibited improved pharmacokinetic properties resulting in a pronounced in vivo efficacy in a mouse septicaemia infection model.
authors.affiliation: F. Hoffmann-La Roche Ltd., Discovery Chemistry, CH-4070 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Angehrn
authors.forename: Erwin
authors.initials: E
authors.lastname: Goetschi
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.forename: Paul
authors.initials: P
authors.lastname: Hebeisen
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Thomas
authors.initials: T
authors.lastname: Luebbers
authors.forename: Peter
authors.initials: P
authors.lastname: Reindl
authors.forename: Fabienne
authors.initials: F
authors.lastname: Ricklin
authors.forename: Anne
authors.initials: A
authors.lastname: Schmitt-Hoffmann
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D027081:DNA Gyrase / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007769:Lactams; D007783:Lactones; D010456:Peptides, Cyclic; D059005:Topoisomerase II Inhibitors; C085889:cyclothialidine; D027081:DNA Gyrase